Disclaimer

"Patent Docs" does not contain any legal advice whatsoever. This weblog is for informational purposes only, and its publication does not create an attorney-client relationship. In addition, nothing on "Patent Docs" constitutes a solicitation for business. This weblog is intended primarily for other attorneys. Moreover, "Patent Docs" is the personal weblog of the Authors; it is not edited by the Authors' employers or clients and, as such, no part of this weblog may be so attributed. All posts on "Patent Docs" should be double-checked for their accuracy and current applicability.

July 04, 2007

Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd. (Fed. Cir. 2007)

Last Thursday, the Federal Circuit upheld a judgment from a District Court that Defendant-Appellant Alphapharm Pty., Inc. had failed to prove invalidity and unenforceability of claims 1, 2, and 5 of U.S. Patent No. 4,687,777 (the '777 patent). Specifically, the Federal Circuit held that the District Court did not err in finding that these claims were not obvious in light of the cited prior art and testimony adduced in deposition and at trial. In a separate appeal on the issue of enforceability, the Federal Circuit entered a judgment of affirmance without opinion under Fed. R. App. P. 36 with respect to the District Court's determination of no inequitable conduct.

Plaintiffs-Appellees Takeda Chemical Industries, Ltd. and Takeda Pharmaceuticals North America, Inc. (Takeda) own the '777 patent, which relates to antidiabetic agents including 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione, which is commonly referred to as pioglitazone. Takeda sells pioglitazone under the trademark Actos®, which is approved for treating Type 2 diabetes.

Seeking approval to market generic pioglitazone, Alphapharm filed an Abbreviated New Drug Application (ANDA) with the FDA. In response, Takeda filed suit against Alphapharm and three other generic drug manufacturers seeking FDA approval to sell generic pioglitazone, alleging that the defendants infringed or would infringe claims 1, 2, and 5 of the '777 patent.

Asserted claim 1 of the '777 patent recites a compound of the formula:

The critical portion of this formula is the ethyl-substituted pyridyl ring (circled), which encompasses four possible compounds in which the ethyl substituent (C2H5) is located at one of four available positions on the pyridyl ring, generating 3-, 4-, 5-, and 6-ethyl compounds. Asserted claim 2 covers pioglitazone, which is referred to as a 5-ethyl compound because the ethyl substituent is attached to the 5-position of the pyridyl ring:

During a bench trial on the issues of validity and enforceability, Alphapharm argued that the claimed compounds would have been obvious at the time of their invention in view of a prior art compound known as "compound b." Compound b possesses a pyridyl ring in which a methyl (CH3) group is attached to the 6-position:

The District Court determined that Alphapharm failed to meet its burden of proving invalidity or inequitable conduct by clear and convincing evidence. With respect to its finding of nonobviousness, the District Court concluded that there was no motivation in the prior art to select compound b as a lead compound for antidiabetic research, and that the prior art actually taught away from using compound b. The District Court also concluded that even if Alphapharm had succeeded in making a prima facie case of obviousness, such a showing would be rebutted by the unexpected results of pioglitazone's nontoxicity. Alphapharm appealed the District Court's determination of validity.

In affirming the District Court's finding of validity, the Federal Circuit determined that:

Alphapharm failed to adduce evidence that compound b would have been selected as the lead compound and, even if that preliminary showing had been made, it failed to show that there existed a reason, based on what was known at the time of the invention, to perform the chemical modifications necessary to achieve the claimed compounds.

Finding that Alphapharm had failed to prove that the claimed compounds would have been prima facie obvious, the Federal Circuit did not find it necessary to also consider objective indicia of nonobviousness.

The Federal Circuit began its analysis by dismissing Alphapharm's assertion that the District Court had misapplied the law relating to obviousness of chemical compounds. Citing In re Dillon, 919 F.2d 688 (Fed. Cir. 1990) and In re Grabiak, 769 F.2d 729 (Fed. Cir. 1985), the Federal Circuit noted that while "structural similarity between claimed and prior art subject matter . . . where the prior art gives reason or motivation to make the claimed compositions, creates a prima facie case of obviousness," a prima facie case of obviousness also requires a showing of "adequate support in the prior art" for the change in structure. The Federal Circuit noted that the test for prima facie obviousness for chemical compounds was also applied in In re Deuel, 51 F.3d 1552 (Fed. Cir. 1995), where the Court observed that "[a] known compound may suggest its homolog, analog, or isomer because such compounds 'often have similar properties and therefore chemists of ordinary skill would ordinarily contemplate making them to try to obtain compounds with improved properties,'" but that "in order to find a prima facie case of unpatentability in such instances, a showing that the 'prior art would have suggested making the specific molecular modifications necessary to achieve the claimed invention' was also required." Finally, the Federal Circuit stated that the test for prima facie obviousness for chemical compounds "is consistent with the legal principles enunciated in KSR," and thus, "in cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound."

Alphapharm's assertion of nonobviousness rested on two key arguments. First, Alphapharm argued that one of ordinary skill in the art would have selected compound b as a lead compound on which to perform further chemical modifications. Second, Alphapharm argued that the skilled artisan would have made two obvious chemical changes to compound b; namely, replacing the methyl group at the 6-position of compound b with an ethyl group (homologation) and moving the ethyl group from the 6-position to other positions on the pyridyl ring (ring-walking) - including the 5-position of pioglitazone.

At trial, the District Court had determined that one of ordinary skill in the art would not have selected compound b as a lead compound. In reaching this finding, the District Court considered the teachings in Takeda's U.S. Patent No. 4,287,200 (the '200 patent), a 1982 article entitled "Studies on Antidiabetic Agents. II. Synthesis of 5-[4-(1-Methylcyclohexylmethoxy)-benzyl]thiazolidine-2,4-dione (ADD-3878) and Its Derivatives" (Sodha et al.), and Takeda's U.S. Patent No. 4,444,779 (the '779 patent).

The '200 patent, which is related to the '777 patent, discloses hundreds of millions of thiazolidinedione compounds and specifically identifies 54 compounds, including compound b, that the inventors synthesized. However, the '200 patent provides no experimental data or test results for the synthesized compounds. In addition, while the prosecution history of the '200 patent provides test results for nine of the synthesized compounds, the District Court determined that the prosecution history did not indicate that any of the nine compounds were superior antidiabetics. Sodha et al. disclose test data relating to 101 thiazolidinedione compounds, including compound b, and identify three compounds deemed most favorable in terms of toxicity and activity. However, none of these favorable compounds is compound b. More importantly, Sodha et al. single out compound b as causing "considerable increases in body weight and brown fat weight." Finally, the '779 patent, which is related to both the '200 and '777 patents, discloses a subset of compounds, including compound b, that were originally disclosed in the '200 patent. The prosecution history of the '779 patent discloses that "the compounds in which these heterocyclic rings are substituted have become important, especially [compound b]."

The District Court concluded that based on the prior art as a whole, one of ordinary skill in the art would not have selected compound b as a lead compound for antidiabetic treatment - notwithstanding the statement in the '779 patent prosecution history - since researchers would have been dissuaded from selecting a lead compound that exhibited negative effects (such as the "considerable increases in body weight and brown fat weight" caused by compound b). The Federal Circuit agreed, concluding that the District Court's fact-findings with respect to the lead compound issue were not clearly erroneous and were supported by evidence in the record.

In addition, the Federal Circuit refused to accept Alphapharm's assertion that KSR International Co. v. Teleflex Inc. or Pfizer, Inc. v. Apotex, Inc. mandated reversal in this case. In contrast with the circumstances in KSR, the Federal Circuit found that in the instant case, "the prior art disclosed a broad selection of compounds any one of which could have been selected as a lead compound for further investigation" as opposed to identifying "predictable solutions" for antidiabetic treatment. The Federal Circuit also noted that compound b "exhibited negative properties that would have directed one of ordinary skill in the art away from that compound." In addition, where the Federal Circuit had determined, in Pfizer, that "the prior art provided 'ample motivation to narrow the genus of 53 pharmaceutically-acceptable anions disclosed by Berge to a few,'" in this case, "the court found nothing in the prior art to narrow the possibilities of a lead compound to compound b."

Finally, with respect to the second ground of Alphapharm's obviousness argument (i.e., that the skilled artisan would have used the steps of homologation and ring walking to synthesize the claimed compounds from compound b), the Federal Circuit concluded that the District Court did not err in determining that one of ordinary skill in the art would not have been prompted to modify compound b. In particular, the Federal Circuit found no error in the District Court's determination that "'homologation had no tendency to decrease unwanted side effects' and thus researchers would have been inclined 'to focus research efforts elsewhere.'" The Federal Circuit also found no error in the District Court's finding that "there was no reasonable expectation in the art that changing the positions of a substituent on a pyridyl ring [via ring walking] would result in beneficial changes."